N-substituted 20-aminopregnan-3-ols, esters thereof, and deta-derivatives corresponding



Sfil3fi8 Patented Dec, 12, E951 ice 3,013,008 N-SUBSTITUTED 20 AMINOPREGNAN-il-OLS, ESTER THEREOF, AND M-DERIVATIVES CGRRESPONDING Raymond E. Counseil, Skokie, IlL, assignor to G. D. Searle & (10., Chicago, 111., a corporation of Delaware No Drawing. Fiied Jan. 9, 1961, Ser. No. 81,254 14 Claims. (Cl. 260-2395) The present invention relates to novel aminosteroids and, more particularly, to N-substituted ZO-aminopregnan-S-ols, their esters, and the corresponding A -deriva tives, which can be represented by the structural formula wherein R is hydrogen or a lower alkanoyl radical, Alk is a lower alkylene radical containing more than one carbon atom and separating the -NH and -Z functions by at least two carbon atoms, and Z is a member of the class comprising hydroxy and di-(lower alkyl)amino radicals, and radicals of the structural formula N )n \K/ wherein X is a bivalent radical selected from the group consisting of methylene, epoxy, and methylimino radicals, and n is O or 1; and the dotted line indicates the optional presence of a doubly-bonded linkage.

The lower alkyl radicals represented supra are typified by methyl, ethyl, propyl, butyl, pentyl, hexyl, and the branched-chain isomers thereof, while the lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain groups isomeric therewith.

The lower alkylene radicals represented by Alk are exemplified by ethylene, trimethylene, tetrarnethylene, pentamethylene, and their branched-chain isomers.

The instant compounds can exist in two stereoisomeric forms in consequence of the alternative oz and ,8 configurations of the substituents at carbon 20. These two isomers in each instance have been related to 20u-aminopregn-S-en-Bfi-ol 3-acetate, disclosed by Corey and Hertler, Journal of the American Chemical Society, 81, 5210 (1959).

Equivalent to the instant organic bases for the purposes of this invention are the corresponding non-tOxic salts as typified by the citrate, tartrate, maleate, ascorbate, gluconate, lactate, succinate, phosphate, sulfate, hydrobromide, and hydrochloride.

The process particularly suitable for the manufacture of the instant compounds of the pregnane series involves treatment of a 3fi-(lower alkanoyl)oxy-S-a-pregnan-ZO- one with the appropriate amine and hydrogen in the presence of a hydrogenation catalyst. A specific example of this process is the reaction of 3fl-acetoxy-5a-pregnan-20- one with fi-dimethylaminoethylamine and hydrogen in the presence of platinum oxide catalyst to afford 20-03- dimethylaminoethyl)aminO-Sa-pregnan 3B oi 3-acetate. Hydrolysis of these esters, typically by means of aqueous sodium hydroxide, results in the corresponding 3,8-ols, which can be separated by fractional crystallization to af-' ford the individual 20m and 20,8-isomersQ An alternate procedure applicable to the preparation of the instant pregnane derivatives involves condensation of a 3,8-(lower alkanoyl)OXy-Sa-pregnan-ZO-one with the amine reactant to form the intermediate substituted imine, which is reduced, under suitable hydrogenation conditions, to the ZO-snbstituted-amino derivative. For example, the aforementioned 3B-acetoxy-Swpregnan-ZO-one and B-dimethylaminoethylamine are allowed to react in the presence of a catalytic quantity of p-toluenesulfonic acid to produce N-(B-dimethylaminoethyl)-3,8-acetoxy 5a pregnan-ZO- imine, which is hydrogenated in the presence of platinum oxide catalyst to afford ZO-(fi-dimethylaminoethyl)amino- 5a-pregnan-3fi-ol, after hydrolysis.

The corresponding A -derivatives encompassed by the present invention can be manufactured by a process utilizing a 20-aminopregn-5-en-3/3-ol or its 3-ester as the start ing material. For example, the Bfi-ol 3-ester is treated with a chloro-substituted alkanoyl chloride to produce the chloroalkylamide, which is converted to the (substituted-amino)alkylamide by treatment with the appropriate amine, then to the desired 20-(substituted-amin0- alkylarnino) derivative by reduction with lithium aluminum hydride. This process is specifically illustrated by the acylation of ZOa-aminOpregn-S-en-3fi-ol 3-acetate with chloroacetyl chloride to aiford 20u-chloroacetamidopregn-5-en-3 8-ol 3-acetate, which is treated with dirnethylamine to produce ZOa-dimethylaminoacetamidopregn-S- en-3B-ol 3-acetate, the reaction of which with a suitable reducing agent such as lithium aluminum hydride results in 20a-( ,B-dimethylaminoethyl) aminopregn-S-en-BB-ol.

When the starting material is a 3 8-01, two molecular equivalents of the chloro-substituted alkanoyl chloride are required, thus producing the bischloro-ester amide. Preferential hydrolysis of the latter substance by treatment with aqueous potassium hydroxide in dioxane affords the free 36-01, which is then converted to the 20- (substit-uted-aminoalkyl)aminopregn-5-en-3/3-ol by treatment first with the substituted-aminoalkylamine, then with lithium aluminum hydride, as described supra. This procedure is exemplified by the reaction of ZOfl-aminopregn-5-en-3B-ol with .two molecular equivalents of chloroacetyl chloride to produce ZOfl-chloroacetamidopregn-5-en-3fi-ol 3-chloroacetate, which is partially hydrolyzed in dioxane with aqueous potassium hydroxide, resulting in 20/8-chloroacetamidopregn-S-en-BB-ol, the treatment of which in butanone with dimethylamine affords 20,6 dimethylaminoacetamidoprcgn 5-en 3B 01, which is treated with lithium aluminum hydride to yield 20fi-( ,B-dimethylaminoethyl) aminopregn-5-en-3B-ol.

The instant 20-(hydroxyalkylamino)pregn-5-en-3B-ols and corresponding 3-esters can be prepared directly from the aforementioned 20-aminopregn-5-en-3p-ols and their esters by reaction with the appropriate alkylene oxide'or alkylene chlorohydrin. Typically, ZOB-amino-pregn-S-en 3 8-0] 3-acetate is allowed to react with ethylene chlorohydrin to yield 20-(fi-hydroxyethyl)aminopregn5-en-3,B o1 3-acetate.

The compounds of this invention are useful as a result of their valuable pharmacological properties. They are, for example, inhibitors of hepatic cholesterol synthesis, cardiac eurhythmic agents, central nervous system depressants, and appetite inhibitors.

The invention is illustrated more fully by the following examples, which are not to be construed as limiting the invention either in spirit or in scope. Temperatures are given in degrees centirgrade (C.) and parts by weight, except as otherwise noted.

Example 1 To a mixture of 72.1 parts of 3fl-acetoxy-5u-pregnam 20-one, 35.2 parts of fl-dimethylarninoethylamine, and 48.04 parts of acetic acid is added 9.2 parts of platinum amaoos oxide and sufficient ethanol to produce a total volume of 1,000 parts. The reaction medium is stirred under hydrogen at approximately 68 atmospheres pressure and a temperature of 45 until the uptake of hydrogen ceases. The catalyst is removed by filtration, then washed with ethanol, and the filtrate is treated with a solution of 60 parts of sodium hydroxide in 200 parts of water, then heated at reflux for about 2 /2 hours. This mixture is cooled, concentrated to approximately A volume, then extracted with chloroform. The organic layer is washed with water, dried over anhydrous potassium carbonate, and concentrated to dryness to afford a residue, which is dissolved in acetone-ether, then treated with isopropanolic hydrogen chloride, With stirring. The resulting precipitate is collected by filtration, washed with acetone, dissolved in aqueous ethanol, and made alkaline by means of 20% aqueous sodium hydroxide. Further dilution with water effects precipitation of the crude product, which is collected by filtration and recrystallized first from acetone,

then from ethyl acetate to yield a ZOa-(fi-dimethylaminoethyl) amino-5a-pregnan-3B-ol, M.P. about 134-136; [a] =+22 (chloroform).

Example 2 The acetone and ethyl acetate mother liquors from Example 1 are concentrated to dryness, and the residue is recrystallized from heptane to yield 205-(B-dimethylaminoethyl) amino-Sa-pregnan-Sfi-ol, M.P. about 74-76"; [a] =+9 (chloroform).

Example 3 To a warm solution of one part of maleic acid in parts of isopropyl alcohol is added a solution of one part of 20w(B-dimethylaminoethyl)amino-5a-pregnan-3fl-ol in 10 parts of isopropyl alcohol, and the resulting mixture is allowed to cool, then filtered to ailord the dimaleate salt, M.P. about 162-164; [a] -=+13.5 (methanol).

Example 4 An isopropanolic solution of ZOB-(fi-dimethylaminoethyl)amino-Sa-pregnan-Sp-Ql is treated with maleic acid according to the procedure of Example 3 to afford the dimaleate salt, M.P. about 172-173; [d]n=+8 (methanol).

Example 5 Example 6 A mixture of 14.42 parts of 3 fi-acetoxy-Sa-pregnan-ZO- one, 9.28 parts of fi-diethylaminoethylamine, 9.6 parts of acetic acid, and 1.2 parts of 10% palladium-on-carbon catalyst, diluted to 165 parts by volume with ethanol, is stirred in a hydrogen atmosphere according to the process described in Example 1. Isolation of the products by the procedure of that example results in 20u-(fi-diethylaminoethyl)amino-5a-pregnan-35-ol, M.P. about 140-142; [a] =+13. From the mother liquors is obtained the p isomer, 20lS-(p-diethylaminoethyl) amino-Se-Pregnan- Bfi-ol.

Example 7 To a mixture of 14.42 parts of 3fi-acetoxy-5a-pregnan- 20-one, 8.16 parts of 'y-dimethylaminopropylamine, and 9.6 parts of acetic acid is added 0.5 part of platinum oxide and a quantity of ethanol sufiicient to achieve a reaction medium of 150 parts by volume. Treatment of this reaction mixture with hydrogen and isolation of the products by the processes described in Example 1 aliords 20acatalyst, and the filtrate (q -dimethylaminopropyl) amino 5a pregnan-3,6 ol and 2018- y-dimethylaminopropyl) amino-5 a-pregnan-Zip-ol.

Treatment of the a-isomer with isopropanolic hydrogen chloride afiords 20a-(q-dimethylaminopropyl) amino-5apregnan-3B-ol dihydrochloride; [a] =+9 (methanol).

Example 8 The substitution of 9.12 parts of fl-pyrroh'dinoethylamine in the procedure of Example 1 results in ZOa-(B- pyrrolidinoethyl) amino-Sa-pregnan 3B ol, M.P. about -147; [a] =+18, and 205-(fl-pyrrolidinoethynamino-Se-pregnan-i: {3-01 monohydrate, M.P. about 69-74;

Example 9 A mixture of 14.42 parts of 3,B-acetoxy-Sa-pregnan-ZO- one, 4.88 parts of fi-hydroxyethylamine, 4.8 parts of acetic acid, and 0.5 part of platinum oxide containing sulficient ethanol to alford a total volume of parts is allowed to react with hydrogen by the procedure of Example 1. Isolation of the crude product by the processes described in that example yields ZO-(B-hydroxyethyl)amino-5ozpregnan-3 13-01, which affords 20a-(B-hydroxyethyDamino- 5a-pregnan-3fi-ol, M.P. about ISO-181 ([a] =+27.2) upon recrystallization from aqueous ethanol.

Example 10 The mother liquors from Example 9 are evaporated to dryness and the residue recrystallized from aqueous ethanol to yield 20B-(fl-hydroxyethyl)amino-Swpregnam 3,6-ol, M.P. about 171-172.5; [e] =+65.

Example 11 Treatment of ZO-(B-hydroxyethyl)amino-Sa-pregnan- 35-01 with isopropanolic hydrogen chloride followed by crystallization of the precipitate from methanol produces 20-(B-hydroxyethyl)amino-Sa-pregnan 3fl-ol hydrochloride hemi-methanolate, M.P. about 283288 (dec.).

Example 12 Treatment of 20f!-(fl-dimethylaminoethyl) amino 5apregnan-SrS-ol with isopropanolic hydrogen chloride results in the corresponding dihydrochloride.

Example 14 A mixture of 14.42 parts of 3 fi-acetoxy-Sa-pregnan-20- one, 4.88 parts of fl-hydroxyethylamine, 4.8 parts ot acetic acid, and 0.5 part of platinum oxide is diluted with ethanol to a volume of 150 parts, then stirred under hydrogen at a pressure of approximately 68 atmospheres and a temperature of about 45 until the uptake of gas ceases. This reaction mixture is cooled, filtered to remove the is treated with isopropanolic hy-' drogen chloride to yield 20-(5-hydroxyethyl)amino-5mpregnan-3 8-ol 3-acetate hydrochloride, M.P. about 242- 244 (dec.).

Example 15 A mixture of 18 parts of 3fi-acetoxy-Sa-pregnan-ZO-one, 8.8 parts of S-dimethylaminoethylamine, and parts of benzene is heated at reflux, during which time the water is removed with the aid of a Dean-Stark water trap. To the mixture is then added 1.8 parts of p-toluenesulfonic acid monohydrate, and reflux is continued for about 3 hours with concomitant removal of water. The reaction mixture is cooled, washed with water, and evaporated to dryness to alford the crude product, which can be recrystallized from heptane to afford pure N-(fi-dimethylaminoethyl)-3fi-acetoxy-5u pregnan 20-imine, M.P. 102-104"; [a] =+37.

To a solution of the latter crude imine in 200 parts of with water, dried purified dioxane is added 1.8 parts of platinum oxide, and this mixture is hydrogenated at room temperature and 4 atmospheres pressure until the absorption of hydrogen ceases. The catalyst is removed by filtration and washed with dioxane, and the filtrate is concentrated to about A volume, then diluted with ether. This organic solution is washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon, and concentrated to dryness in vacuo to afford an oily residue. A solution of this residue in 160 parts of methanol is treated with a solution of 4 parts of sodium hydroxide in 20 parts of water, and the resulting mixture is heated at reflux for about 2 hours, then stored at room temperature for about 15 hours, and poured slowly into ice water. This aqueous mixture is extracted with methylene chloride, and the organic layer is dried over anhydrous sodium sulfate, then evaporated to dryness to yield a residue, which is dissolved in acetone and treated with isopropanolic hydrogen chloride. The resulting precipitate is collected by filtration, washed with ether, and dried to produce 20-(,8- dimethylaminoethyl)amino-5oz pregnan 35-01 dihydrochloride.

A solution of the latter dihydrochloride in aqueous ethanol is made alkaline by the addition of aqueous sodium hydroxide, then poured slowly, with stirring, into ice water. The resulting precipitate is collected by filtration, washed with water, and fractionally crystallized from ethyl acetate to ailord 20a-(,8 dimethylaminoethyl)amino- 5a-pregnan-3/8-ol, identical with the product of Example 1, and 20,8-(fi-dimethylaminoethyl)amino Six-pregnan- 3,B-ol, identical with the product of Example 2.

Example I 6 To a solution of 18 parts of 20u-aminopregn 5-en-313-01 3-acetate in 240 parts of benzene containing 7.3 parts of triethylamine is added dropwise a solution of 7.5 parts of chloroacetyl chloride in 20 parts of benzene, and this mixture is stirred and heated at reflux for about one hour, then cooled and filtered. The filter cake is washed with benzene, and the filtrate is washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate containing decolorizing carbon, and stripped of solvent at reduced pres sure. The residue is crystallized from ethanol to yield 20a-chloroacetamidopregn 5 en-3,B-ol 3-acetate, M.P. about 196-199"; [a] =-44.

Example 17 a To a solution of 8.72 parts of 20u-chloroacetamidopregn-5-en-3B-ol 3-acetate in 87 parts of toluene containing 20 parts of butanone is added a solution of 9 parts of dimethylamine in 26 parts of toluene, and this mixture is heated at 5055 in a suitable sealed container for about 40 hours. The reaction mixture is cooled, washed over anhydrous potassium carbonate containing decolorizing carbon, and evaporated to dryness at reduced pressure. The resulting residue is crystallized from heptane to produce 20a-dimethylaminoacetamidopregn-5-en-3/3-ol 3-acetate, M.P. about 1595-1615"; [a] =52.5.

To a slurry of 3.8 parts of lithium aluminum hydride in 75 parts of purified dioxane is added, with stirring a solution of 8.8 parts of 20oZ-dimethylaminoacetamidopregn-5-en-3fi-ol 3-acetate in 100 parts of purified dioxane, and the reaction mixture is heated at reflux with stirring for about 18 hours, then cooled to -5, and treated successively with 50 parts of dioxane containing 4 parts of water, 3 parts of 20% aqueous sodium hydroxide, and 14 parts of water. The resulting precipitated salts are removed by filtration, and the filtrate is poured slowly into ice water to effect precipitation of the crude product, which is collected by filtration and recrystallized from acetone-hexane to yield pure ZOu-(B-dimethyIaminO- ethyl)aminopregn en 3B o1, M.P. about 83-87; [a] =4l.

6 Example 18 To a solution of 0.5 part of ZOa-(B-dimethyIaminoethyl)aminopregn-S-en-Bfi-ol in 10 parts of ethanol is added 0.25 part of concentrated hydrochloric acid and 0.1 part of platinum oxide, and the reaction mixture is Example 19 Treatment of 20a (fl diethylaminoethyl)amino 5apregnan-3,8-ol with isopropanolic hydrogen chloride and recrystallization of the crude product from methanol-ethyl acetate atfords the corresponding dihydrochloride, M.P. about 250-260 (dec.).

Example 20 Example 21 The substitution of 15.9 parts of ZOp-aminO-pregn-S-en- 35-01 and 16.9 parts of fi-chloropropionyl chloride in the process of Example 16 results in 20,8-(fl-chloropropionamido) pregn-S -en-3 ,8-01 3- (achloropropionate) Example 22 Example 23 The reaction of 8.1 parts of ZOB-(fi-chloropropionamido)pregn-5-en-3fl-ol with 14.6 parts of diethylamine according to the procedure of Example 17 results in 20B-(fi-diethylaminopropionamido)pregn-5-en-3,B-ol, 8.8 parts of which is treated with lithiumaluminum hydride by the process described in that example to yield 20/3- (v-diethylaminopropyl) aminopregn-5-en-3/3-ol.

Example 24 A solution of 9 parts of 20a-chloroacetamidopregn- 5-en-35-ol 3-acetate and'4.4 parts of diethylamine in 154 parts of benzene is heated at 5055 in a suitable sealed container for about 48 hours. The cooled mixture is filtered, and the filtrate is evaporated to dryness in vacuo.

Crystallization of the solid residue from aqueous methanol afiords 20u-diethylaminoacetamidopregn5-en-3,B-ol 3-acetate, M.P. about 147-149'...

Example 25 To a refluxing slurry of 3.5 parts of lithium aluminum hydride in 100 parts of purified dioxane, under nitrogen, is added 6.9 parts of 20a-diethylaminoacetamidopregn-S- en-3fi-ol 3-acetate dissolved in parts of purified dioxane over a period of about 1 /2 hours. Reflux is contained 3-(fi-chloropropionate) in 250 I 7 for about 20 hours, and the reaction mixture is cooled to about -5, then treated successively with 2.5 parts of dioxane containing 3.5 parts of water, 2.63 parts of 20% aqueous sodium hydroxide, and 11.9 parts of water. The precipitated salts are removed by filtration, and the filtrate is stripped of solvent at reduced pressure to afford a residue, which is crystallized from acetone to yield pure 20a-(p-diethylaminoethyl) aminopregn-S en 313-01, M.P. about 130132.

Example 26 A solution of 4.4 parts of 20e-chloroacetamido-pregn- -en-3,6ol 'S-acetate and 1.7 parts of pyrrolidine in 44 parts of benzene is heated at reflux for about 20 hours, then allowed to cool to room temperatures and diluted with ether. The organic mixture is Washed with water,

dried over anhydrous potassium carbonate containing decolorizing carbon, and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from aqueous ethanol to yield pure 20u-pyrrolidinoacetamidopregn-S-en-S'B-ol 3-acetate, M.P. about 157-160".

Example 27 The process of Example 25 is used to convert 20o:- pyrrolidinoacetamidopregn-S-en-3 8-ol S-acetate to 20- (dpyrrolidinoethyl)aminopregn-5-en-3B-ol, M.P. about 111-1135".

Example 28 The reaction of 20e-(B-pyrrolidinoethyl)aminopregn- 5-en-3 8-ol with maleic acid by the procedure of Exampie 3, and recrystallization of the crude salt from acetonemethanol results in the corresponding pure dimaleate, M.P. about 164-167.

Example 29 An equivalent quantity of piperidine is substituted in the procedure of Example 26 to produce a material, which is recrystallized from methanol to afford 20ozpiperidinoacetamidopregn-S-en-Brfi-ol 3-acetate, M.P. about Example 30 The substitution of an equivalent quantity of 20mpiperidinoacetamidopregn-S-en-313-ol 3'-acetate in the process described in Example 25 results in ZOa-(fi-piperidinoethyl) aminopregn-S-en-Sfi-ol, M.P. about 142-1435.

Example 31 By substituting an equivalent quantity of morpholine and otherwise proceeding according to the herein described processes of Example 26, ZOa-morpholinoacetamidopregn-S-en-Bfi-ol 3-acetate, M.P. about 173-176", is obtained.

Example 32 I The reaction of an equivalent quantity of 20tx-mor pholinoacetamidopregn-S-en-3fi-ol S-acetate with lithium aluminum hydride by the process described in Example 25 affords 20a (B-rnorpholinoethyl) aminopregn-5-en-3 3-ol, M.P. about 145.5-147".

Example 33 -ZOa-(B-morpholinoethyl)aminopregn-S-emBfi-ol is al lowed to react with maleic acid according to the procedure of Example 3 to yield the dimaleate, M.P. about Example v34 The substitution of an equivalent quantity of N-methylpiperazine in the procedure of Example 26 results in 200:- [(N-methylpiperazino) acetamido] pregn-5-en-3fl-ol 3-ace-' tate, obtained as an oil.

Example 35 An equivalent quantity of 20a[(N-methylpiperazinolacetamido]pregn-S-en-3B-ol B-acetate is substituted in the procedure of Example 25 to yield ZOa-[fi-(N-methylpiperaziuoethyl)anuno]pregn-5-en-3fi ol, M.P. about 147- 148.

Example 36 The substitution of an equivalent quantity of 3/3-propionoxy-Su-pregnan-ZO-one in the process of Example 14 results in ZO-(fi-hydroxyethyl) amino-Sa-pregnan-BB-ol 3-propionate.

What is claimed is: l. A compound of the structural formula CH3 OHNEAllt-Z CH3 wherein R is selected from the group consisting of hydrogen and lower alkanoyl radicals, Alk is a lower alkylene radical containing more than one carbon atom and separating the NH and -Z functions by at least two carbon atoms, Z is selected from the group consisting of hydroxy and di- (lower alkyhamino radicals and radicals of the structural formula wherein X is selected from the group consisting of methylene, epoxy, and methylirnino radicals and n is selected from the group consisting of 0 and l, and the dotted line indicates the optional presence of a doubly-bonded linkage between carbon atoms 5 and 6.

2. A compound of the structural formula wherein Alk is a lower alkylene radical containing more wherein Alk is a lower alkylene radical containing more than one carbon atom and separating the -NH and functions by at least two carbon atoms, and R is a lower ,13. ZO-(fl-morpholinoethyl)aminopregn-S-en-IiB-ol. alkyl radical. 14. 20- [,B-(N-methylpiperazinoethyl) aminoJ-pregn-S- 5. 20- ,B-diethylaminoethyl) amino-5 a-p-regnan-3 [3-01.

6. ZO-(B-hydroxyethyl)amino-5a-pregnan-3B-o-I. 5 References Cited in the file of this patent 7. ZO-(flpyrrolidinoethyl)amino-5a-pregnan-3B-ol. UNITED STATES PATENTS 8. 20-(fl-dimethylaminoethyl)amino5a-pregnan-3,B-ol.

9. 20-(fi-dimethylaminoethyl)aminopregn-5-en-3/3-ol. et a1 g 10. 20-(B-diethylaminoethyl)aminopregn-5-en-3fl-ol. u

11. ZO-(B-pyrrolidinoethyl)aminopregn-5-en-3fi-ol. 10 OTHER REFERENCES 12. ZO-(fi-piperidinoethyl) aminopregn-S-en-Iifi-ol. Corey et aL: J. Am. Chem. Soc., vol. 80, 2903 (1958). 

1. A COMPOUND OF THE STRUCTURAL FORMULA 